This invention relates to novel piperazine derivatives, to their use and to pharmaceutical compositions containing them. The novel compounds are useful as 5-HT1A binding agents, particularly as 5-HT1A receptor antagonists.
U.S. Pat. No. 6,127,357 discloses compounds of the general formula (I): 
and pharmaceutically acceptable acid addition salts thereof wherein:
A is alkylene chain of 2 to 4 carbon atoms optionally substituted by one or more lower alkyl groups,
Z is oxygen or sulfur,
R is H or lower alkyl,
R1 is a mono or bicyclic aryl or heteroaryl radical,
R2 is a mono or bicyclic heteroaryl radical, and
R3 is hydrogen, lower alkyl, cycloalkyl, cycloalkenyl, cycloalkyl(lower)alkyl, aryl, aryl(lower)alkyl, heteroaryl, heteroaryl(lower)alkyl, a group of formula xe2x80x94NR4R5 [where R4 is hydrogen, lower alkyl, aryl or aryl(lower)alkyl and R5 is hydrogen, lower alkyl, xe2x80x94CO(lower)alkyl, aryl, xe2x80x94Coaryl, aryl(lower)alkyl, cycloalkyl, or cycloalkyl-(lower)alkyl or R4 and R5 together with the nitrogen atom to which they are both attached represent a saturated hytrocyclic ring which may contain a further heteroatom], or a group of formula OR6 [where R6 is lower alkyl, cycloalkyl, cycloalkyl(lower)alkyl, aryl, aryl(lower)alkyl, heteroaryl or heteroaryl(lower)alkyl].
WO 97/03982 discloses compounds of the general formula (II): 
including enantiomers and the pharmaceutically acceptable acid addition salts thereof.
The compounds of formula (II) fall within the disclosure of U.S. Pat. No. 6,127,357 but are not specifically disclosed therein. Compounds of Formula II were taught to have potent 5-HT1A antagonist activity in vivo when administered by the oral route.
Novel compounds of the invention have the structural formula (III): 
wherein R1 is cyano, nitro, trifluoromethyl or halogen, or pharmaceutically acceptable acid addition salts thereof.
Halogen, as used herein, refers to chlorine, fluorine, bromine and iodine.
The compounds of Formula III contain an asymmetric carbon atom. Accordingly, they may exist in different stereoisomeric forms. In some preferred embodiments the R stereoisomer (Formula IIIa) is preferred. 
In accordance with some embodiments of the invention, the (R) stereoisomer is substantially free of the (S) stereoisomer. Substantially free, as used herein means that the compound is made up of a significantly greater proportion of its (R) stereoisomer than the (S) stereoisomer. In preferred embodiments the compound is made up of at least about 90% by weight of its (R) stereoisomer and about 10% by weight or less of its (S) stereoisomer. In other embodiments of the invention, the compound is made up of at least about 99% by weight of its (S) stereoisomer and about 1% by weight or less of the (R) stereoisomer. Preferred stereoisomers may be isolated from racemic mixtures by any method known to those skilled in the art, including high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts. See, for example, Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S. H. Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind. 1972).
The most preferred compounds of the invention are (R)-4-Cyano-N-{2-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]propyl}-N-pyridin-2-yl-benzamide; and pharmaceutically acceptable acid addition salts thereof.
The pharmaceutically acceptable salts are the acid addition salts which can be formed from a compound of the above general formula and a pharmaceutically acceptable acid such as, for example, benzoic, phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic, malic, mandelic, mucic, nitric, fumaric, succinic, tartaric, acetic, lactic, pamoic, pantothenic, benzenesulfonic, or methanesulfonic acid. In some embodiments of the invention the preferred acid addition salt is hydrochloric acid.
The compounds of the present invention can be prepared by known methods from known starting materials which are available by conventional methods. For example the compounds may be prepared by the general methods disclosed in EP-A-0512755 and WO 97/03982.
Such disclosed methods include acylating an amine of formula (IV) with a known benzoyl chloride (V) or an alternative acylating derivative thereof. Examples of acylating derivatives include the acid anhydride, imidazolides (e.g. obtained form carbonyldiimidazole), or activated esters. 
wherein R1 is cyano, halogen, trifluoromethyl or nitro.
Novel compounds of the present invention are potent 5-HT1A binding agents which selectively binds to the 5-HT1A receptor. Furthermore, the novel compounds of the invention are 5-HT1A receptor antagonists when tested by standard pharmacological procedures.
In addition, the novel compounds of formula (III) are unique from previously disclosed 5HT1A receptor antagonists in that they possess a superior duration of action as a 5-HT1A receptor antagonist when administered in vivo.